MTH1

MTH1 inhibitors and degraders target nudix hydrolase 1 (NUDT1, also called MTH1), which removes oxidized nucleotides. MTH1 hydrolyzes oxidized precursors such as 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dGTP), which keeps them out of newly synthesized DNA. In 2014 TH588 and TH287 were introduced as MTH1 inhibitors that increase oxidative damage in cancer cell DNA. A second 2014 study showed that (S)-crizotinib, the enantiomer of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib, binds MTH1 stereospecifically. Later selective inhibitors such as BAY-707 and IACS-4619 were used to reexamine whether MTH1 inhibition alone reduces cancer cell survival. SU0383 inhibits both MTH1 and 8-oxoguanine DNA glycosylase 1 (OGG1). aTAG 4531 and aTAG 2139 are MTH1-binding degraders used to remove MTH1-tagged fusion proteins in targeted degradation studies.